Olumiant ® (baricitinib)

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Olumiant® (baricitinib): were malignancies reported during alopecia areata clinical trials?

As of March 2021, 2 malignancies and 1 non-melanoma skin cancer (NMSC) were reported in baricitinib-treated patients (n=1244). The data do not suggest an increased risk for malignancies or NNMSC in the baricitinib vs placebo group in alopecia areata.

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Warnings and precautions related to malignancy

The risk of malignancies including lymphoma is increased in patients with rheumatoid arthritis. Immunomodulatory medicinal products may increase the risk of malignancies including lymphoma. The clinical data are insufficient to assess the potential incidence of malignancies following exposure to baricitinib. Long-term safety evaluations are ongoing.1

Baricitinib genotoxicity and carcinogenicity

Non-clinical data reveal no special hazard for humans based on conventional studies of

  • safety pharmacology,
  • genotoxicity and
  • carcinogenic potential.1

Baricitinib was not genotoxic in the

  • bacterial mutagenicity assay (Ames assay)
  • in vitro chromosomal aberration assay using cultured human lymphocytes, or
  • in vivo micronucleus assay in the rat.2,3

Baricitinib did not produce neoplastic changes in 2-year rat and 6-month transgenic mouse carcinogenicity studies.2,3

Risk of malignancies in patients with alopecia areata

The association between AA and cancer has not been extensively studied and appears to vary based on the type of malignancy.

Published literature reported that AA was associated with an increased risk for thyroid cancer.4-7

Conversely, a minimal or rather negative association was found between AA and other malignancies.4-9

Alopecia areata clinical trial criteria related to malignancies

Patients were excluded from enrollment in the BRAVE-AA1 and BRAVE-AA2 studies if they had

  • a history of lymphoproliferative disease
  • signs or symptoms suggestive of possible lymphoproliferative disease, including lymphadenopathy or splenomegaly
  • an active primary or recurrent malignant disease, or
  • been in remission from clinically significant malignancy for <5 years.10

Patients were allowed to participate in the BRAVE-AA1 and BRAVE-AA2 studies if they had

  • cervical carcinoma in situ that has been successfully treated with no evidence of recurrence or metastatic disease for ≥3 years, or
  • basal cell or squamous cell skin cancers that have been successfully treated with no evidence of recurrence for ≥3 years.10

Patients were discontinued from study drug if a treatment-emergent malignancy occurred during the clinical trials. However, patients with successfully treated basal or squamous cell skin carcinoma could continue on study drug.2

Incidence of malignancies in the baricitinib alopecia areata clinical trials

The baricitinib alopecia areata (AA) clinical trial program includes

The incidence of malignancies in the BRAVE-AA trials was reported in 3 integrated safety datasets, including the

  • 36-week placebo-controlled BARI AA dataset with patients exposed to placebo, baricitinib 2 mg and baricitinib 4 mg from randomization to week 36
  • extended BARI AA dataset with patients exposed to baricitinib 2 mg or 4 mg from randomization to dose or treatment change, or data cut-off, and
  • All-BARI-AA dataset with all patients exposed to any baricitinib dose (1-mg, 2-mg, or 4-mg) at any time during the studies.13

Safety data were integrated from the BRAVE-AA1 Phase 2 and 3 cohorts (data cut-off March 31, 2021) and from BRAVE-AA2 (data cut-off March 24, 2021.13

More details on patient exposure and censoring rules in each dataset are provided in Integrated Analysis Datasets Used to Evaluate Safety in Alopecia Areata Clinical Trials .

According to standard conventions, the reporting for malignancy was broken into subcategories for malignancies, excluding NMSC and NMSC, each with its own set of preferred terms from the standardized Medical Dictionary for Regulatory Activities (MedDRA) query (SMQ).2

The incidence of malignancies excluding NMSC and NMSC across the 3 integrated safety datasets is presented in Incidence of Malignancies From the 36-Week Placebo-Controlled Period, Extended, and All BARI Integrated Datasets.

Incidence of Malignancies From the 36-Week Placebo-Controlled Period, Extended, and All BARI Integrated Datasets13

Event

36-Week Placebo-Controlled BARI AA
n (%) [IR]

Extended BARI AA
n (%) [IR]

All BARI AA
n (%) [IR]

Placebo
(n=371)

BARI 2 mg
(n=365)

BARI 4 mg
(n=540)

BARI 2 mg
(n=365)

BARI 4 mg
(n=540)

All Doses
(N=1244)

Malignancies excluding NMSCa

1 (0.3) [0.4]

0

1 (0.2) [0.3]

0

2 (0.4) [0.3]

2 (0.2) [0.1]

NMSCb

0

0

0

1 (0.3) [0.3]

0

1 (0.1) [0.1]

Abbreviations: AA = alopecia areata; BARI = baricitinib; IR = incidence rate; NMSC = nonmelanoma skin cancer.

Data cutoff: March 24, 2021 for BRAVE-AA1 and March 31, 2021 for BRAVE-AA2.

aEvents of prostate cancer in the placebo arm and B-cell lymphoma and breast cancer in the baricitinib 4-mg arm.

bEvent of squamous cell carcinoma of the skin.

Malignancy excluding nonmelanoma skin cancer

As described in Incidence of Malignancies From the 36-Week Placebo-Controlled Period, Extended, and All BARI Integrated Datasets, during the 36-week placebo-controlled period, 1 event of prostate cancer was reported by a patient in the placebo arm approximately 6 months after study entry. One patient also reported an event of B-cell lymphoma approximately 4 months after the start of baricitinib 4 mg.2,13

During the extended evaluation period, 1 patient reported breast cancer approximately 10 months after starting baricitinib 4 mg.2,13

After diagnosis, all patients were discontinued from the study drug and study.2

No additional patient reported a malignancy excluding NMSC in the All-BARI-AA dataset.13

Nonmelanoma skin cancer

As described in Incidence of Malignancies From the 36-Week Placebo-Controlled Period, Extended, and All BARI Integrated Datasets, no NMSC was reported during the 36-week placebo-controlled period.13

During the extended evaluation period, 1 patient reported an event of squamous cell carcinoma of skin approximately 1 year and 4 months after starting baricitinib.2,13

This patient was successfully treated by surgery and no action was taken with the study drug.2

No additional patients reported NMSC in the All-BARI-AA dataset.13

Description integrated safety datasets

Integrated Analysis Datasets Used to Evaluate Safety in Alopecia Areata Clinical Trials2,13 

Analysis Set

Description

36-Week placebo-controlled BARI AA

Assesses BARI 4 mg, BARI 2 mg, and placebo.

Includes patients from the phase 2/3 BRAVE-AA1 and phase 3 BRAVE-AA2 studies who were randomized to

  • BARI 4 mg (n=540, PYE=363.4)
  • BARI 2 mg (n=365, PYE=240.6), or
  • placebo (n=371, PYE=243.2).

Evaluation time period included randomization to week 36.

Extended BARI AA

Assesses BARI 4 mg and BARI 2 mg including extended evaluations.

Includes patients from the phase 2/3 BRAVE-AA1 and phase 3 BRAVE-AA2 studies who were randomized to

  • BARI 4 mg (n=540, PYE=624.3), or
  • BARI 2 mg (n=365, PYE=371.5).

Evaluation time period included randomization up to data cutoff, March 24, 2021 for BRAVE-AA2 and March 31, 2021 for BRAVE-AA1. Data were censored after a patient was switched to another dose or treatment.

All BARI AA

No between-group assessments.

Includes 1244 (total PYE=1362.2) patients from the phase 2/3 BRAVE-AA1 and phase 3 BRAVE-AA2 studies who were exposed to any BARI dose, including

  • BARI 4 mg (n=938, PYE=858.9)
  • BARI 2 mg (n=564, PYE=488.9), or
  • BARI 1 mg (n=28, PYE=14.6).

Evaluation time period included any time points during the studies either from randomization or from switch or rescue from placebo.

Abbreviations: AA = alopecia areata; BARI = baricitinib; PYE = patient-years of exposure.

Note: BARI 1 mg was studied in pivotal trials, however it is not approved. Please refer to section 4.2 of the Olumiant Summary of Product Characteristics for approved dosage.

References

1Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2Data on file, Eli Lilly and Company and/or one of its subsidiaries.

3Carfagna M, Cannady E, Ryan T, et al. Carcinogenicity assessment of baricitinib in Tg.rasH2 mice and Sprague-Dawley (Crl:CD) rats. Regul Toxicol Pharmacol. 2018;92:458-471. https://www.ncbi.nlm.nih.gov/pubmed/29203403

4Lee JH, Song Y, Do Han K, et al. Cancer risk by the subtype of alopecia. Sci Rep. 2018;8(1):9748. https://doi.org/10.1038/s41598-018-28142-1

5Lee S, Lee H, Lee CH, Lee WS. Comorbidities in alopecia areata: a systematic review and meta-analysis. J Am Acad Dermatol. 2019;80(2):466-477.e16. https://doi.org/10.1016/j.jaad.2018.07.013

6Seo HM, Han SS, Kim JS. Cancer risks among patients with alopecia areata: a population-based case-control study in Korea. J Am Acad Dermatol. 2018;78(1):209-211. https://doi.org/10.1016/j.jaad.2017.08.011

7Phan K, Smith SD. Alopecia areata and risk of cancer varies based on type of malignancy. J Am Acad Dermatol. 2021;85(suppl 3):AB25. https://dx.doi.org/10.1016/j.jaad.2021.06.126

8Conic RZ, Rambhia P, Atanaskova-Mesinkovska N, et al. Lack of an association between alopecia areata and visceral or hematopoietic cancers. J Am Acad Dermatol. 2017;77(5):981-982. https://doi.org/10.1016/j.jaad.2017.06.045

9Chen CC, Chang YT, Liu HN, Chen YJ. Cancer risk in patients with alopecia areata: a nationwide population-based matched cohort study. Cancer Med. 2018;7(5):2153-2159. https://doi.org/10.1002/cam4.1448

10King B, Ohyama M, Kwon O, et al; BRAVE-AA investigators. Two phase 3 trials of baricitinib for alopecia areata. N Engl J Med. 2022;386(18):1687-1699. https://doi.org/10.1056/nejmoa2110343

11A study of baricitinib (LY3009104) in adults with severe or very severe alopecia areata (BRAVE-AA2). ClinicalTrials.gov identifier: NCT03899259. Updated January 26, 2022. Accessed March 4, 2022. https://clinicaltrials.gov/ct2/show/NCT03899259

12A study of baricitinib (LY3009104) in participants with severe or very severe alopecia areata (BRAVE-AA1). ClinicalTrials.gov identifier: NCT03570749. Updated February 3, 2022. Accessed March 4, 2022. https://clinicaltrials.gov/ct2/show/study/NCT03570749

13King B, Mostaghimi A, Shimomura Y, et al. Integrated safety analysis of baricitinib in adults with severe alopecia areata from two randomized clinical trials. Poster presented at: Annual Meeting of the American Academy of Dermatology Association (AAD); March 25-29, 2022; Boston, MA. Accessed April 29, 2022. https://aad-eposters.s3.amazonaws.com/AM2022/poster/33966/Integrated+safety+analysis+of+baricitinib+in+adults+with+severe+alopecia+areata+from+two+randomized+clinical+trials.pdf

Date of Last Review: 26 January 2022


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